Nilotinib, or 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-N-[5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)phenyl]benzamide, of the following structure is a small molecule tyrosine kinase inhibitor which can be used for the treatment of certain neoplastic diseases, such as Philadelphia Chromosome Chronic myelogenous leukemia.

The method for the preparation of Nilotinib was first disclosed in the U.S. Pat. No. 7,169,791 B2 (the '791 patent), which involves the coupling of an acid, 4-methyl-3[[4-(3-pyridinyl)-2-pyrimidinyl]amino]benzoic acid, with an aniline derivative 5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)benzenamine using excessive diethyl cyanophosphonate as a coupling reagent.
The general reaction scheme of the process disclosed by the '791 patent is illustrated as follows:

This process, however, gives low and inconsistent yields and the coupling reagent, diethyl cyanophosphonate, is an expensive reagent.
An improved process for the preparation of Nilotinib was later disclosed by the U.S. Patent 2008/0188656 (the '656 patent). The general reaction scheme of this improved process is illustrated as follows:

According to the '656 patent, Nilotinib is prepared by direct condensation of an ester derivative with the same aniline molecule disclosed in the '791 patent. The reaction is catalyzed by a strong base and carried out in an organic solvent. When the strong base potassium tert-Butoxide is used as the coupling reagent in solvent tetrahydrofuran, a free base Nilotinib can be produced in reasonable yield.
This improved process is repeatable at temperatures ranging from 0˜40° C. and Nilotinib can be obtained after 22 hours at 75% conversion. Detail results are shown in Table 1.
TABLE 1Coupling reaction by reagent t-BuOK in THFEq. ofNilotinibEster/Temp.Time(Area %)EntryamineCoupling Reagent(° C.)(h)(By HPLC)Patent ′7911.0/1.0t-BuOK (5.5 eq.)18-23NA67% (Isolate)11.0/1.0 t-BuOK (5.5 eq.)01.075.703.073.006.073.9022.075.121.0/1.0t-BuOK (5.5 eq.)201.072.3203.072.4206.072.52022.075.131.0/1.0 t-BuOK (5.5 eq.)401.072.2403.071.8406.074.34022.074.9